ABSTRACT Lung cancer is the leading cause of cancer death. Cigarette smoking is the most important causal factor. The smoking cessation program and antismoking campaign over the past 50 years has reduced the prevalence of cigarette smoking by two-thirds in the US. Currently there are more former smokers than current smokers. However, former smokers remain at high risk of lung cancer even after quitting smoking for many years. Majority new lung cancer cases occur among former smokers. Unfortunately preventive intervention for lung cancer among former smokers is still lacking. This proposed proof-of-principal study is to evaluate the chemopreventive potentials of sulforaphane, a natural product formed from glucoraphanin in certain cruciferous vegetables, on reducing the cellular and molecular risk biomarkers of lung cancer pathogenesis. Sulforaphane and other isothiocyanates derived from cruciferous vegetables have shown promising chemopreventive properties in preclinical animal experiments, and in epidemiological studies and short-term randomized clinical trials in humans. Dietary intake of sulforaphane significantly reduced the incidence of tobacco-carcinogen induced lung adenocarcinoma in animal models that mimicked the scenario as former smokers, along with the concurrent reduction of cell proliferation marker Ki-67 and the increase of apoptosis markers caspase-3 and TUNEL. In short-term clinical trials in humans, intake of sulforaphane enhanced the detoxification of environmental carcinogens and reduced Ki-67 index. Epidemiological studies demonstrated that high intake of cruciferous vegetables or isothiocyanates was associated signficantly with reduced risk of lung cancer in humans. However, clinical trials with a relatively long-term treatment of sulforaphane on the modulation of lung cancer pathogenesis biomarkers are lacking. This proposed randomized, double-blinded, placebo-controlled, phase 2 clinical trial will enroll 72 former smokers at high risk for lung cancer. All subjects will be randomly assigned to either treatment (daily minimal dose of 120 mol sulforaphane for 12 months) or placebo. Bronchoscopy-guided bronchial biopsy and brushing, bronchoalveolar lavage, and nasal brushing, blood and urine samples will be collected pre- and post- intervention. The specific aims are (1) to determine if sulforphane modulates the changes of bronchial dysplasia index, cell proliferation marker Ki-67, and apoptosis markers caspase-3 and TUNEL in bronchial biopsies, all of which have shown to be directly associated with lung cancer pathogenesis; and (2) to determine if sulforaphane modulate the changes of the gene expression markers in bronchial and nasal epithelia that have been shown to be directly linked to the development of lung cancer. The findings of the proposed study will have significant public health implication in reducing lung cancer incidence and mortality in former smokers. The ultimate goal is to develop, evaluate, and validate the efficacy of this readily available, widely accessible, inexpensive, natural compound as a primary chemopreventive agent.